Compositions and methods for immunomodulation

Abstract

The invention relates to methods and reagents for the treatment of immunological diseases. In particular, the invention relates to isoforms of the C4b-binding protein (C4BP) lacking beta chains as well as to fragments and peptides derived thereof and to the uses of these polypeptides for the treatment of immunological diseases such as immunoinflammatory disease, sepsis, an autoimmune disease, transplant rejection, graft-versus-host disease and a hypersensitivity disease. Moreover, the invention relates also the use of factor H for the treatment of immunological diseases. In addition, the invention relates to tolerogenic dendritic cells obtained using the C4BP isoform lacking beta chain, the peptides and fragments thereof and factor H and to the therapeutic uses of said cells.

The invention claimed is: 
     
       1. A method for the treatment of an immunological disease caused by an undesired activation of the immune system by increasing tolerogenic dendritic cell and/or regulatory T cell populations in a subject in need thereof comprising the administration to said subject of a C4BP isoform lacking the beta chain wherein if at least one of the alpha-chains forming said isoform is a deletion mutant which lacks at least one of the CCP regions, the CCP6 region is preserved in said alpha-chain. 
     
     
       2. The method according to  claim 1  wherein all the alpha chains in the C4BP isoform are full-length alpha-chains. 
     
     
       3. The method according to  claim 1 , wherein the immunological disease is selected from an immunoinflammatory disease and an autoimmune disease. 
     
     
       4. The method according to  claim 1 , wherein the immunological disease is selected from the group consisting of rheumatoid arthritis, graft-versus-host disease, systemic lupus erythematosus, and ulcerative colitis. 
     
     
       5. A method for the treatment of an immunological disease caused by an undesired activation of the immune system by increasing tolerogenic dendritic cell and/or regulatory T cell populations in a subject in need thereof comprising the administration to said subject of a C4BP isoform lacking the beta chain, wherein the C4BP isoform is selected from the group consisting of α 7 β 0  and α 6 β 0 . 
     
     
       6. The method according to  claim 5 , wherein the immunological disease is selected from the group consisting of an immunoinflammatory disease, sepsis, an autoimmune disease, transplant rejection, graft-versus-host disease and a hypersensitivity disease. 
     
     
       7. The method according to  claim 6  wherein the immunological disease is selected from the group consisting of:
 (i) an immunoinflammatory disease selected from the group consisting of infarct or stroke, atherosclerosis, pulmonary fibrosis, acute respiratory distress syndrome, asthma, cancer, pre-eclampsia and eclampsia; 
 (ii) sepsis; 
 (iii) an autoimmune disease selected from the group consisting of: autoimmune blood diseases, autoimmune diseases of the musculature, autoimmune diseases of the ear, autoimmune eye diseases, autoimmune diseases of the kidney, autoimmune skin diseases, cardiovascular autoimmune diseases, endocrine autoimmune diseases, autoimmune gastroenteric diseases, autoimmune nervous diseases and a systemic autoimmune disease selected from the group consisting of systemic lupus erythematosus, antiphospholid syndrome, autoimmune lymphoproliferative disease, autoimmune polyendocrinopathy, Bechet's disease, Goodpasture's disease, sarcoidosis, scleroderma, Sjogren's syndrome and psoriasis; 
 (iv) transplant rejection; 
 (v) graft-versus-host disease; and 
 (vi) a hypersensitivity disease. 
 
     
     
       8. The method according to  claim 7  wherein the autoimmune blood disease is selected from the group consisting of pernicious anemia, autoimmune hemolytic anemia, aplastic anemia, idiopathic thrombocytopenic purpura and ankylosing spondylitis; the autoimmune disease of the musculature is selected from the group consisting of polymyositis and dermatomyositis; the autoimmune disease of the ear is selected from the group consisting of autoimmune hearing loss and Meniere's syndrome; the autoimmune eye disease is selected from the group consisting of Mooren's disease, Reiter's syndrome and Vogt-Koyanagi-Harada disease; the autoimmune disease of the kidney is selected from the group consisting of glomerulonephritis and IgA nephropathy; the autoimmune skin disease is selected from the group consisting of pemphigus or autoimmune bullous diseases, pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, bullous pemphigoid, vitiligo, epidermolysis bullosa acquisita, psoriasis and alopecia areata; the cardiovascular autoimmune disease is selected from the group consisting of autoimmune myocarditis, vasculitis, Churg-Strauss syndrome, giant cells arteritis, Kawasaki's disease, polyarteritis nodosa, Takayasu's arteritis and Wegener's granulomatosis; the endocrine autoimmune disease is selected from the group consisting of Addison's disease, autoimmune hypoparathyroidism, autoimmune hypophysitis, autoimmune oophoritis, autoimmune orchitis, Grave's Disease, Hashimoto's thyroiditis, polyglandular autoimmune syndrome type 1 (PAS-I), polyglandular autoimmune syndrome type 2 (PAS-2) and polyglandular autoimmune syndrome type 3 (PAS-3); the autoimmune gastroenteric disease is selected from the group consisting of autoimmune hepatitis, primary biliary cirrhosis, inflammatory bowel disease, celiac disease and Crohn's disease; the autoimmune nervous disease is selected from the group consisting of multiple sclerosis, myasthenia gravis, Guillan-Barre syndrome and chronic inflammatory demyelinating neuropathy. 
     
     
       9. The method according to  claim 7  wherein the autoimmune disease is systemic lupus erythematosus. 
     
     
       10. The method according to  claim 7  wherein the immunological disease is transplant rejection. 
     
     
       11. The method according to  claim 7  wherein the immunological disease is graft-versus-host disease. 
     
     
       12. The method according to  claim 7  wherein the autoimmune disease is an autoimmune disease of the kidney. 
     
     
       13. A preventive method for the treatment of a subject at risk for developing an immunological disease by increasing tolerogenic dendritic cell and/or regulatory T cell populations, comprising:
 the administration to said subject of a C4BP isoform lacking the beta chain, 
 wherein if at least one of the alpha-chains forming said isoform is a deletion mutant which lacks at least one of the CCP regions, the CCP6 region is preserved in said alpha-chain; 
 wherein said immunological disease is caused by an undesired activation of the immune system. 
 
     
     
       14. A method for preventing the release of an inflammatory cytokine from dendritic cells in a subject in need thereof, comprising:
 the administration to said subject of a C4BP isoform lacking the beta chain, 
 wherein if at least one of the alpha-chains forming said isoform is a deletion mutant which lacks at least one of the CCP regions, the CCP6 region is preserved in said alpha-chain; 
 wherein said inflammatory cytokine is IL-12p70, TNF-α, IFN-γ, or a combination thereof. 
 
     
     
       15. A preventive method for the treatment of a subject at risk for developing an immunological disease by increasing tolerogenic dendritic cell and/or regulatory T cell populations, comprising:
 the administration to said subject of a C4BP isoform lacking the beta chain, wherein the C4BP isoform is selected from the group consisting of α 7 β 0  and α 6 β 0 ; 
 wherein said immunological disease is caused by an undesired activation of the immune system. 
 
     
     
       16. A method for preventing an increase in expression of a dendritic cell surface marker in a subject in need thereof, comprising:
 the administration to said subject of a C4BP isoform lacking the beta chain, 
 wherein if at least one of the alpha-chains forming said isoform is a deletion mutant which lacks at least one of the CCP regions, the CCP6 region is preserved in said alpha-chain; 
 wherein said dendritic cell surface marker is CD83, CD86, or a combination thereof.